Rheumatoid arthritis (RA) is one of the most common crippling diseases to affect Americans. With up to two million adults affected, this disease represents hundreds of millions of dollars of medical expenses and lost income. While the etiology of this disease is complex, the consistent association with HLA class II antigens (DR) indicates that these immune response genes are likely to be implicated. In addition, recent DNA studies suggest an association between certain highly polymorphic regions of the DR gene and risk of RA. However, these association studies have yet to be unambiguously confirmed by genetic linkage studies, since these latter studies have failed to give consistent results. It is very likely that this ambiguity is due to the fact that genetic susceptibility to RA results from an interaction between HLA and other immune response genes. This project is designed to quantify the extent to which genetic susceptibility to RA is due to interaction between specific immune response genes. This overall objective will be achieved by carrying out four interrelated specific aims within a population that is both ethnically and sociodemographically homogeneous. We will first identify and contact every diagnosed case of RA resident in the study area (Utah and surrounding regions). Second, the extent of familial aggregation of disease in this population will be assessed by a combination of questionnaires and followup clinical exam. Third, we will carry out a matched case-control study of 60 multiplex probands (patients with affected relatives), 120 simplex probands (patients without affected relatives) and 120 random controls to determine whether the population risk of disease is due to interaction between different immune response genes. This analysis will include an evaluation of DNA sequence differences at the DR region. Fourth, we will carry out a detailed clinical, serological and genetic (DNA and HLA) evaluation of approximately 1,140 individuals representing the families of these 60 probands to determine the extent to which interaction between immune response genes within pedigrees influences the familial distribution of RA.